Fibroblast growth factor control of cartilage homeostasis

Abstract

Osteoarthritis (OA) and degenerative disc disease (DDD) are similar diseases involving the breakdown of cartilage tissue, and a better understanding of the underlying biochemical processes involved in cartilage degeneration may allow for the development of novel biologic therapies aimed at slowing the disease process. Three members of the fibroblast growth factor (FGF) family, FGF-2, FGF-18, and FGF-8, have been implicated as contributing factors in cartilage homeostasis. The role of FGF-2 is controversial in both articular and intervertebral disc (IVD) cartilage as it has been associated with species- and age-dependent anabolic or catabolic events. Recent evidence suggests that FGF-2 selectively activates FGF receptor 1 (FGFR1) to exert catabolic effects in human articular chondrocytes and IVD tissue via upregulation of matrix-degrading enzyme production, inhibition of extracellular matrix (ECM) accumulation and proteoglycan synthesis, and clustering of cells characteristic of arthritic states. FGF-18, on the other hand, most likely exerts anabolic effects in human articular chondrocytes by activating the FGFR3 pathway, inducing ECM formation and chondrogenic cell differentiation, and inhibiting cell proliferation. These changes result in dispersed chondrocytes or disc cells surrounded by abundant matrix. The role of FGF-8 has recently been identified as a catabolic mediator in rat and rabbit articular cartilage, but its precise biological impact on human adult articular cartilage or IVD tissue remains unknown. The available evidence reveals the promise of FGF-2/FGFR1 antagonists, FGF-18/FGFR3 agonists, and FGF-8 antagonists (i.e., anti-FGF-8 antibody) as potential therapies to prevent cartilage degeneration and/or promote cartilage regeneration and repair in the future.

Genomic Analysis and Differential Expression of HMG and S100A Family in Human Arthritis: Upregulated Expression of Chemokines, IL-8 and Nitric Oxide by HMGB1

“…Indeed, OGN -/ -mice showed an increased diameter of collagen fibrils (Tasheva et al, 2002). FGF-18, which signals through FGF receptor 3, promotes chondrogenesis (Ellman et al, 2013). A recombinant version of FGF-18 (sprifermin) may enter clinical trials as a potential treatment for OA (Ellman et al, 2013).…”

“…FGF-18, which signals through FGF receptor 3, promotes chondrogenesis (Ellman et al, 2013). A recombinant version of FGF-18 (sprifermin) may enter clinical trials as a potential treatment for OA (Ellman et al, 2013). VEGF couples hypertrophic cartilage remodeling, ossification, and angiogenesis during endochondral bone formation, proliferation, differentiation, and/or survival of osteoclasts, osteoblasts, and chondrocytes (Hans-Peter et al, 1999;Carlevaro et al, 2000;Murata et al, 2008).…”

Cartilage regeneration for treatment of osteoarthritis: a paradigm for nonsurgical intervention

“…Of these, FGFs have become significant, and FGF-2 and FGF-18 are the most studied. FGF-2, through its interaction with FGF receptor (FGFR)-1, promotes cartilage degradation and the engagement with FGFR-3 drives joint protection [Ellman et al 2013]. In mouse models, FGF-2 delays cartilage degradation.…”

Lumbar Disc Degeneration is Facilitated by MiR-100-Mediated FGFR3 Suppression

“…FGFR1 and FGFR3 compete with each other for FGF2 bindings [18,19]. Hence, FGFR3 is suggested to have a negative effect on FGF2-mediated MMP13 expression [18,19]. However, the exact underlying molecular mechanisms are largely unknown.…”

“…These FGFRs consist of a cellular ligand domain composed of three immunoglobulin-like domains, a single transmembrane helix domain, and an intracellular domain with tyrosine kinase activity to mediate signal transduction after their binding to FGF ligands [15][16][17]. FGFR1 and FGFR3 compete with each other for FGF2 bindings [18,19]. Hence, FGFR3 is suggested to have a negative effect on FGF2-mediated MMP13 expression [18,19].…”